The present invention relates to a novel class of substituted indane or dihydroindole compounds having effects at dopamine D4 receptors. The compounds are either selective dopamine D4 ligands or they have combined effects at dopamine D4 and serotonergic receptors and/or the serotonergic transporter. These compounds are therefore useful in the treatment of certain psychiatric and neurologic disorders, including psychosis, depression and anxiety.
Related compounds are known from WO patents Nos. WO 9421627-A1, WO 9421630-A1, WO 94 21626-A1 describing various series of indolyl- or indazolylmethyl piperidine or piperazine derivatives as selective dopamine D4 antagonists. No data are given. The compounds are only said to give Ki values of less than 1.5 xcexcM in a test for displacement of 3H spiperone from human dopamine D4 receptor subtypes in clonal cell lines.
EP patent No. 574313 A1 describes compounds with piperidine, tetrahydropyridine, or piperazine rings substituted in position 1 and 4 with various aryl or heteroaryl groups, including certain 1-(indane or indanemethyl)piperidine, tetrahydropyridine, or piperazine derivates substituted in the 4-position with 1,4-benzodioxane. The compounds are claimed to have effects at dopamine D2 and D4 receptors.
Dopamine D4 receptors belong to the dopamine D2 receptor family considered to be responsible for antipsychotic effects of neuroleptics. Furthermore, dopamine D4 receptors are primarily located in areas of the brain other than striatum (Van Tol, et al. Nature, 1991, 350, 610), the low level in striatum suggesting lack of extrapyramidal activity. Also, dopamine D4 receptor levels have been reported to be elevated in schizophrenic patients (Seeman et al., Nature, 1993, 365, 441.) and the antipsychotic clozapine which is lacking extrapyramidal side effects, has a high affinity for dopamine D4 receptors (Van Tol, et al. Nature, 1991, 350, 610.)
Various effects are known with respect to compounds which are ligands at the different serotonin receptor subtypes. As regards the 5-HT2A receptor which was previously referred to as the 5-HT2 receptor, the following effects have e.g. been reported:
Antidepressive effect, improvement of the sleep quality (Meert, T. F.; Janssen, P. A. J. Drug. Dev. Res. 1989, 18, 119.) and the negative symptoms of schizophrenia and reduction of extrapyramidal side-effects caused by treatment with classical neuroleptics in schizophrenic patients (Gelders, Y. G., British J. Psychiatry, 1989, 155 (suppl. 5, 33). Finally, selective 5-HT2A antagonists could be effective in the prophylaxis and treatment of migraine (Scrip Report; xe2x80x9cMigrainexe2x80x94Current trends in research and treatmentxe2x80x9d; PJB Publications Ltd.; May 1991).
Clinical studies have shown that 5-HT1A partial agonists are useful in the treatment of anxiety disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder (Glitz, D. A., Pohl, R., Drugs 1991, 41, 11). Preclinical studies indicate that also full agonists are useful in the treatment of the above mentioned anxiety related disorders (Schipper, Human Psychopharmacol., 1991, 6, 853).
There is also evidence, both clinical and preclinical, in support of the beneficial effect of 5-HT1A partial agonists in the treatment of depression, impulse control disorders and alcohol abuse (van Hest, Psychopharmacol., 1992, 107, 474; Schipper et al, Human Psychopharmacol., 1991, 6, S53; Cervo et al, Eur. J. Pharm., 1988, 158, 53; Glitz and Poh, Drugs 1991, 41, 11; Grofet al., Int. Clin. Psychopharmacol. 1993, 8, 167-172; Ansseau et al, Human Psychopharmacol. 1993, 8, 279-283).
5-HT1A agonists and partial agonists inhibit isolation induced aggression in male mice indicating that these compounds are useful in the treatment of aggression (Sanchez et al., Psychopharmacology, 1993, 110, 53-59).
Furthermore, 5-HT1A ligands have been reported to show antipsychotic effect in animal models (Wadenberg and Ahlenius, J. Neural. Transm., 1991t 83, 43; Ahlenius, Pharmacol. and Toxicol., 1989, 64, 3; Lowe et al., J. Med. Chem., 1991, 34, 1860; New et al., J. Med. Chem., 1989, 32, 1147; and Martin et al., J. Med. Chem., 1989, 32, 1052).
Recent studies also indicate that 5-HT1A receptors are important in the serotonergic modulation of haloperidol-induced catalepsy (Hicks, Life Science 1990, 47, 1609, Wadenberg et al. Pharmacol. Biochem. and Behav. 1994, 47, 509-513) suggesting that 5-HT1A agonists are useful in the treatment of EPS induced by conventional antipsychotic agents such as haloperidol.
5-HT1A agonists have shown neuroprotective properties in rodent models of focal and global cerebral ischaemia and may, therefore, be useful in the treatment of ischaemic disease states (Prehn , Eur. J. Pharm. 1991, 203, 213).
Pharmacological studies have been presented indicating that 5-HT1A antagonists are useful in the treatment of senile dementia (Bowen et al, Trends Neur. Sci. 1992, 15, 84).
5-HT reuptake inhibitors are well known antidepressant drugs.
Accordingly, dopamine D4 receptor ligands are potential drugs for the treatment of psychosis and positive symptoms of schizophrenia and compounds with combined effects at dopamine D4 and serotonergic receptors may have the further benefit of improved effects on other psychiatric symptoms in schizophrenic patients such as depressive and anxiety symptoms. As 5-HT1A and 5-HT2A receptor ligand classes of compounds and 5-HT reuptake inhibitors have different activities in different animal models predictive of anxiolytic and antiaggressive effects (Perregaard et al., Recent Developments in Anxiolytics. Current Opinion in Therapeutic Patents 1993, 1, 101-128) and/or in models predictive of effects in other psychic disorders it might also be highly beneficial to have such combined serotonergic effects.
The object of the invention is to provide compounds with dopamine D4 activities or with combined effects at dopamine D4 receptors and serotonergic receptors and/or the serotonergic transporter.
It has now been found that certain substituted indane or dihydroindole compounds have effects at dopamine D4 receptors. Additionally, many of the compounds interact with central serotonergic receptors, in particular with the 5-HT1A and/or the 5-HT2A receptors and/or they act as 5-HT reuptake inhibitors.
Accordingly, the present invention relates to novel compounds of the formula I. 
wherein A and B are independently O or S;
D is a methylene group optionally substituted with one or two C1-4 alkyl groups;
Y is a hydrocarbon group completing an indane ring, a group NR1 completing a dihydroindole ring, or a group N completing a dihydroindole ring attached via the 1-position;
W is a bond, and n+m is 1, 2, 3, 4, 5, or 6;
W is CO, SO, or SO2, n is 2, 3, 4, or 5 and m is 0, 1, 2, or 3, provided that n+m is not more than 6; or
W is O, S, n is 2, 3, 4, or 5 and m is 0, 1, 2, or 3, provided that n+m is not more than 6, and
provided that when Y is N completing a dihydroindole ring attached via the 1-position then m is 2, or 3; and when Y is NR1 completing a dihydroindole ring linked via the 2-position then m is 1, 2, or 3;
the dotted line, emanating from X, indicates an optional bond; when it does not indicate a bond X is N, CH or COH; and when it indicates a bond X is C;
R1 is selected from
hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalk(en)yl, C3-8 cycloalk(en)yl-C1-6 alk(en/yn)yl, aryl, heteroaryl, aryl-C1-6 alkyl, heteroaryl-C1-6 alkyl, acyl, thioacyl, C1-6 alkylsulfonyl, trifluoromethylsulfonyl, arylsulfonyl or heteroarylsulfonyl, or
R15VCOxe2x80x94 wherein V is O or S and R15 is C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-6 alkyl, aryl or heteroaryl, or
a group R16R17NCOxe2x80x94 or R16R17NCSxe2x80x94 wherein R16 and R17 are independently hydrogen, C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-C1-6 alkyl, aryl or heteroaryl, or R16 and R17 together with the N-atom to which they are linked, form a pyrrolidinyl, piperidinyl or perhydroazepin group;
R2-R5 are independently selected from hydrogen, halogen, cyano, nitro, C1-6 alk(en/yn)yl, C1-6 alkoxy, C1-6 alkylthio, hydroxy, C3-8 cycloalk(en)yl, C3-8 cycloalk(en)yl-C1-6 alk(en/yn)yl, C1-6 alkylcarbonyl, phenylcarbonyl, halogen substituted phenylcarbonyl, trifluoromethyl, trifluoromethylsulfonyloxy and C1-6 alkylsulfonyl, one of R2-R5 alternatively being a group xe2x80x94NR13R14 wherein R13 is selected from the R1 substituents; R14 is hydrogen, C1-6 alkyl, C2-6, alkenyl, C2-6, alkynyl, C3-8 cycloalk(en)yl, C3-8, cycloalk(en)yl-C1-6 alk(en/yn)yl, aryl, heteroaryl, aryl-C1-6 alkyl or heteroaryl-C1-6 alkyl, or R13 and R14 together with the N-atom to which they are linked form a group 
wherein Q is Cxe2x95x90O, Cxe2x95x90S or CH2; T is NH, S, O or CH2; and p is 1-4, inclusive;
or two adjacent groups taken from R2 -R5 may be joined and designate a xe2x80x94(CH2)3xe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94NHxe2x80x94 thereby forming a fused 5-membered ring;
R6-R8 are independently hydrogen, halogen, cyano, nitro, C1-6-alk(en/yn)yl, C1-6-alkoxy, C1-6-alkylthio, hydroxy, trifluoromethyl, or C1-6 alkylsulfonyl;
with the proviso that the substituent R3 or R4 in 6-position may not be xe2x80x94NR13R14 when Y is CH2 and the ring is linked via the 1-position; and pharmaceutically acceptable acid addition salts thereof.
The compounds of the invention have been found to show high affinity for dopamine D4 receptors and some of the compounds were found also to show affinity for serotonergic receptors including 5-HT1A receptors and/or for 5-HT2A receptors. In addition to the effects at these receptor subtypes, certain of the present compounds also show 5-HT reuptake inhibiting effect.
Accordingly, the compounds of the invention are considered useful in the treatment of positive and negative symptoms of schizophrenia, other psychoses, anxiety disorders, such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, depression, alcohol abuse, impulse control disorders, aggression, side effects induced by conventional antipsychotic agents, ischaemic disease states, migraine, senile dementia and cardiovascular disorders and in the improvement of sleep.
In another aspect the invention provides a pharmaceutical composition comprising at least one compound of Formula I as defined above or a pharmaceutically acceptable acid addition salt thereof or prodrug thereof in a therapeutically effective amount and in combination with one or more pharmaceutically acceptable carriers or diluents.
In a further aspect the present invention provides the use of a compound of Formula I as defined above or an acid addition salt or prodrug thereof for the manufacture of a pharmaceutical preparation for the treatment of the above mentioned disorders.